Ovarian cancer is the most lethal gynecologic malignancy, with almost 14,000 women in the United States expected to die of the disease in 2003 [Jemal]. Unfortunately, there is no effective means for detection of early ovarian cancer, and as such over 75% of cases are diagnosed when the disease has spread to the upper abdomen or lymph nodes. Despite intensive cytotoxic chemotherapy following radical surgery to reduce ovarian cancer volume, the median survival of women with advanced and large-volume ovarian cancer is under 40 months [McGuire].
Recent studies have demonstrated the critical role of angiogenesis in tumor development and the formation of metastatic tumor deposits. The inhibition of tumor angiogenesis has emerged as a promising new therapeutic modality. A number of biologic activities have been identified as being involved in this complex process, however, vascular endothelial growth factor (VEGF) is now known to be one of the most potent and specific pro-angiogenic factors responsible for tumor-induced angiogenesis [Leung], and is the most promising target for inhibition of tumor-induced angiogenesis. VEGF is overexpressed in a number of human solid malignancies, including ovarian cancer [Boocock, Olson]. VEGF overexpression has also been demonstrated in women with ovarian cancer and has been shown to be a poor prognostic factor [Hollingsworth, Paley, Tempfer]. Thus, VEGF is a rational target against which immunization may have a role in the treatment or prevention of ovarian cancer.
Various strategies have been used to inhibit the function of VEGF. These include targeting the VEGF receptor (VEGFR), using gene therapy techniques that deliver antisense oligonucleotides, use of soluble VEGFR, development of receptor tyrosine kinase (RTK) inhibitors, and monoclonal antibodies (Mab) directed against VEGF [Kim]. The most promising approach appears to be a recombinant humanized version of a murine anti-human VEGF Mab (rhuMab VEGF, Bevacizumab). This Mab has been tested in patients with metastatic cancer [Gordon, Margolin]. There are, however, several disadvantages to the use of antibody therapy. Importantly, passive immunization strategies involve the transfer of antibody to the patient, and immunity is short-lived as the antibodies are cleared from the circulation. Likewise, Mabs are often immunogenic themselves, thereby limiting their long-term use. Also, large antibody volumes are necessary for effective sustained immunization.
The use of vaccines to prevent or treat ovarian cancer is a highly attractive approach because of the expected minimal side effects of vaccine therapy. Many cancers express tumor-associated antigens (TAA) that serve as targets for cancer vaccines. Strategies for immunization have included whole cell vaccines, protein and DNA vaccines, as well as peptide vaccines; each type of antitumor vaccine has its advantages and limitations. Peptides are an attractive anticancer vaccine in that they are safe (free of pathogens and oncogenic potential), stable, easily constructed, and are a cost-effective vaccine system [Dakappagari, Peoples, Kaumaya]. Importantly, peptide vaccines lead to sustained immune responses and memory, unlike that from passive immunization. Limitations of peptide vaccines include the fact that unmodified peptides are rarely immunogenic; thus rational peptide design is imperative to the development of an effective antitumor vaccine.